Is Alzheimer disease a disease?

Nature Reviews Neurology, Год журнала: 2024, Номер 20(4), С. 245 - 251

Опубликована: Фев. 29, 2024

Язык: Английский

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CryoET of β-amyloid and tau within postmortem Alzheimer’s disease brain

Nature, Год журнала: 2024, Номер 631(8022), С. 913 - 919

Опубликована: Июль 10, 2024

Abstract A defining pathological feature of most neurodegenerative diseases is the assembly proteins into amyloid that form disease-specific structures 1 . In Alzheimer’s disease, this characterized by deposition β-amyloid and tau with conformations. The in situ structure human brain unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out cryo-electron tomography, we determined in-tissue architectures pathology a postmortem disease donor brain. plaques contained mixture fibrils, some which were branched, protofilaments, arranged parallel arrays lattice-like structures. Extracellular vesicles cuboidal particles defined non-amyloid constituents plaques. By contrast, inclusions formed clusters unbranched filaments. Subtomogram averaging cluster 136 filaments single tomogram revealed polypeptide backbone conformation filament polarity orientation paired helical within tissue. Filaments similar to each other, but different between clusters, showing heterogeneity spatially organized subcellular location. structural approaches outlined here for tissues have applications broad range diseases.

Язык: Английский

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New insights in animal models of neurotoxicity-induced neurodegeneration

Frontiers in Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Янв. 8, 2024

The high prevalence of neurodegenerative diseases is an unintended consequence the longevity population, together with lack effective preventive and therapeutic options. There great pressure on preclinical research, both old new models are required to increase pipeline drugs for clinical testing. We review here main neurotoxicity-based animal leading central neurodegeneration. Our focus was studying how changes in neurotransmission neuroinflammation, mainly rodent models, contribute harmful processes linked majority currently use mimic Parkinson's disease (PD) Alzheimer's (AD), which most common conditions older adults. AD age-related dementia, whereas PD movement disorder also cases dementia. Several natural toxins xenobiotic agents induce dopaminergic neurodegeneration can reproduce neuropathological traits PD. literature analysis MPTP, 6-OH-dopamine, rotenone suggested latter as a useful model when specific doses were administrated systemically C57BL/6 mice. Cholinergic modelled toxin scopolamine, screening protective against cognitive decline AD. have been used neuroinflammation-based dementia AD, including lipopolysaccharide (LPS), streptozotocin, monomeric C-reactive protein. bacterial agent LPS makes testing anti-inflammatory therapies halt development severity However, neurotoxin might be more than genetic drug discovery but that not case where they cannot beat developments transgenic mouse models. Overall, we should work using all available either

Язык: Английский

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The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Май 17, 2023

Abstract Amyloid plaques composed of Aβ fibrils are a hallmark Alzheimer’s disease (AD). However, the molecular architecture amyloid in context fresh mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report situ App NL-G-F familial AD mouse model containing Arctic mutation an atomic ex vivo purified fibrils. We show that in-tissue arranged lattice or parallel bundles, interdigitated by subcellular compartments, extracellular vesicles, droplets multilamellar bodies. The fibril differs significantly from earlier NL-F structure, indicating striking effect mutation. These structural data also revealed ensemble additional fibrillar species, including thin protofilament-like rods branched Together, these results provide for dense network characterises β-amyloid plaque pathology.

Язык: Английский

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New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5383 - 5383

Опубликована: Март 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Язык: Английский

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Magnetic Resonance Elastography in the Study of Neurodegenerative Diseases

Journal of Magnetic Resonance Imaging, Год журнала: 2023, Номер 59(1), С. 82 - 96

Опубликована: Апрель 21, 2023

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's (PD) present a major health burden to society. Changes in brain structure cognition are generally only observed at the late stage of disease. Although advanced magnetic resonance imaging (MRI) techniques diffusion may allow identification biomarkers earlier stages neurodegeneration, early diagnosis is still challenging. Magnetic elastography (MRE) noninvasive MRI technique for studying mechanical properties tissues by measuring wave propagation induced using purpose‐built actuator. Here, we systematic review preclinical clinical studies which MRE has been applied study neurodegenerative diseases. Actuator systems data acquisition, inversion algorithms analysis, sample demographics described tissue stiffness measures obtained whole internal structures summarized. A total six animal eight human have published. The refer 123 experimental animals (68 AD 55 PD) 121 wild‐type animals, while 142 patients with (including 56 17 166 controls. consistent reporting decreased hippocampal region mice. However, terms progression, although decreases either storage modulus or shear magnitude reported brain, there variation results region. reports significant decrease magnitude, both PD different affected their infancy, future it will be interesting investigate potential relationships between measures, help elucidate mechanisms underlying onset progression Evidence Level 1. Technical Efficacy Stage 2.

Язык: Английский

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Updates in Alzheimer's disease: from basic research to diagnosis and therapies

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Сен. 4, 2024

Язык: Английский

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Neuroinflammation in Alzheimer disease

Nature reviews. Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Язык: Английский

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The Brain–Gut Axis, an Important Player in Alzheimer and Parkinson Disease: A Narrative Review

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(14), С. 4130 - 4130

Опубликована: Июль 15, 2024

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s (PD), are severe age-related disorders with complex multifactorial causes. Recent research suggests a critical link between neurodegeneration the gut microbiome, via gut–brain communication pathway. This review examines role of trimethylamine N-oxide (TMAO), microbiota-derived metabolite, in development AD PD, investigates its interaction microRNAs (miRNAs) along this bidirectional TMAO, which is produced from dietary metabolites like choline carnitine, has been linked to increased neuroinflammation, protein misfolding, cognitive decline. In AD, elevated TMAO levels associated amyloid-beta tau pathologies, blood–brain barrier disruption, neuronal death. can cross promote aggregation amyloid proteins. Similarly, affects alpha-synuclein conformation aggregation, hallmark PD. also activates pro-inflammatory pathways NF-kB signaling, exacerbating neuroinflammation further. Moreover, modulates expression various miRNAs that involved neurodegenerative processes. Thus, microbiome–miRNA–brain axis represents newly discovered mechanistic dysbiosis neurodegeneration. MiRNAs regulate key oxidative stress, death, contributing progression. As direct consequence, specific miRNA signatures may serve potential biomarkers for early detection monitoring PD aims elucidate interrelationships microbiota, trimethylamine-N-oxide (miRNAs), central nervous system, implications these connections diseases. context, an overview current neuroradiology techniques available studying animal models used investigate intricate pathologies will be provided. summary, bulk evidence supports concept modulating pathway through changes, manipulation and/or miRNA-based therapies offer novel approaches implementing treatment debilitating neurological disorders.

Язык: Английский

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Genetically modified non-human primate models for research on neurodegenerative diseases

动物学研究, Год журнала: 2024, Номер 45(2), С. 263 - 274

Опубликована: Янв. 1, 2024

Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS). Currently, there no therapies available can delay, stop, or reverse the pathological progression NDs in clinical settings. As population ages, imposing huge burden on public health systems affected families. Animal models important tools for preclinical investigations to understand pathogenesis test potential treatments. While numerous rodent have been developed enhance our understanding mechanisms, limited success translating findings from animal practice suggests is still need bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, vervet monkeys, phylogenetically, physiologically, biochemically, behaviorally most relevant humans. This particularly evident similarity structure function their central nervous systems, rendering species uniquely valuable neuroscience research. Recently, development several genetically modified NHP has successfully recapitulated key pathologies revealed novel mechanisms. review focuses efficacy NHPs modeling insights gained, well challenges associated with generation complexities involved subsequent analysis.

Язык: Английский

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